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Title: Tricyclic GyrB/ParE (TriBE) Inhibitors. A new class of broad-spectrum dual-targeting antibacterial agents

Journal Article · · PLoS ONE
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  1. Trius Therapeutics, San Diego, CA (United States)
  2. ViviSource Labs., Waltham, MA (United States)
  3. MIcromyx LLC., Kalamazoo, MI (United States)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
  5. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
+ Show Author Affiliations

Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. Growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Moreover, lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.

Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC52-07NA27344
OSTI ID:
1237527
Report Number(s):
LLNL-JRNL-637252
Journal Information:
PLoS ONE, Vol. 8, Issue 12; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 70 works
Citation information provided by
Web of Science

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Cited By (11)

Antibiotics book November 2017
Synthesis and Evaluation of N -Phenylpyrrolamides as DNA Gyrase B Inhibitors journal January 2018
Machine learning-powered antibiotics phenotypic drug discovery journal March 2019
New N -phenyl-4,5-dibromopyrrolamides as DNA gyrase B inhibitors journal January 2019
The challenge of converting Gram-positive-only compounds into broad-spectrum antibiotics: Challenges in developing broad-spectrum antibiotics journal February 2018
Mutant Alleles of lptD Increase the Permeability of Pseudomonas aeruginosa and Define Determinants of Intrinsic Resistance to Antibiotics journal November 2015
A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections journal December 2014
Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis journal November 2017
Targeting bacterial topoisomerases: how to counter mechanisms of resistance journal June 2016
Dual Protonophore–Chitinase Inhibitors Dramatically Affect O. volvulus Molting journal June 2014
Insights into Newer Antimicrobial Agents against Gram-negative Bacteria journal January 2016

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